Composition and method for treating glaucoma



United States Patent 3,467,756 COMPOSITION AND METHOD FOR TREATING GLAUCOMA Clement A. Stone, Blue Bell, Pa., assignor to Merck & Co. Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed Mar. 16, 1967, Ser. No. 623,540 Int. Cl. A61k 27/00 US. Cl. 424-283 2 Claims ABSTRACT OF THE DISCLOSURE Anti-glaucoma compositions containing, in an opthalmic vehicle, 10,11-dihydro-5-(3-methylaminopropyl)-5, -epoxy-1l-hydroxy-SH-dibenzo[a,d]cycloheptene or 10, 1 1-dihydro-5-(3-dimethylaminopropyl)-5,10-epoxy-5H-dibenzo[a,d] cycloheptene-ll-hydroxy-imino (or non-toxic addition salts thereof), either singly or in combination with a sympathomimetic amine, as well as methods of treatment.

The present invention relates to topical opthalmic compositions useful in the treatment of glaucoma. More particularly, this invention relates to anti-glaucoma agents which effectively lower intraocular pressure and to methods for the preparation and administration of such compositions.

Present therapeutic methods for the treatment of glaucoma predominantly involve the use of miotics, carbonic anhydrase inhibitors and surgery. Of these methods the most widely employed for glaucoma therapy is the topical use of miotics, pilocarpine being the most usually employed miotic. This drug generally requires an undesirable frequency of instillation, generally around the clock. Furthermore, tolerance to the drug, requiring increasingly stronger solutions, often up to the highest dosage level usable, and tachyphylaxis are not uncommon disadvantages. Carbonic anhydrase inhibitors are generally not employed as a sole therapeutic measure, but mainly are used concomitantly with miotics in the treat ment of chronic glaucoma or preparatory to surgery. Surgery is usually reserved for those cases of chronic glaucoma that do not respond to drug therapy or for the treatment of the somewhat uncommon acute congestive glaucoma. To complete the picture of presently available methods for the treatment of glaucoma, one should mention the anti-cholinesterases. These topical preparations are longer lasting therapeutically than pilocarpine, but unfortunately, produce intense miosis, occasional iris cysts and have been associated with parasympathomimetic systemic eflects. Lastly, it can be mentioned that miotics produce a miosis which is generally annoying to the patient because of interference with vision. It, therefore, is quite obvious that there is an outstanding need for new therapeutic agents which can be employed in the treatment of glaucoma and which avoid some or all of the disadvantages of the presently available measures.

It is, therefore, a significant purpose of this invention to provide such novel anti-glaucoma compositions. A further object is to topically administer such compositions to the eye in a dosage form that will significantly lower intraocular pressure while achieving the pupillary goals of a submaximally dilated and mobile pupil, retaining sensitivity to stimulation by light. These and other objects of this invention appear more fully hereinafter.

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The topical anti-glaucoma compositions of this invention contain one of the following compounds as novel intraocular hypotensive agents:

10,11-dihydro-5- 3-methylamin0propyl) -5,10-ep0xy-11-hydroxy-5H-dibenzo [a,d]cyc1oheptene IROH 1 \i/ CH3 CHzCHzCHzN 10,11-dihydro-5 (3-dimethylaminopropyl) -5,10-epoxy-5H- dibenzo a,d] cyclohep tene-ll-hydroxy-imino in a conventional topical opthalmic vehicle and in an effective dosage range which upon ocular introduction will lower intraocular pressure. Although the above formulae show the free base, it is to be understood that the nontoxic acid addition salts, such as hydrochloride or hydrogenmaleate, are equivalent for the purposes of this invention.

Although compositions of this invention wherein the novel hypotensive agents form the only active ingredient effectively lower intraoclar tension, for some purposes it may be desirable to combine treatment with exogenous sympathomirnetic amines. In one embodiment the sympathomimetic amine can be administered with the intraocular hypotensive agent of this invention in a single vehicle in dosages which effectively lower intraocular pressure. Exemplary of such sympathomimetic amines are epinephrine, norepinephrine and isoproterenol. In another embodiment the sympathomimetic amine can be administered following instillation of the novel hypotensive agent of this invention.

The compositions of this invention are administered topically to the eye, either in the form of opthalmic solutions, or as opthalmic ointments. Formulations are herein expressed as percent weight by volume and generally the dosages for the intraocular hypotensive agent fall within the range of 0.01 to 0.02 percent. Higher dosages, as for example, up to about 0.2 percent, or lower dosages can be employed, provided the dose is effective in lowering intraocular pressure, is non-irritating and achieves the desired pupillary goals previously set forth.

The procedure for the preparation of the compounds of claim 1 as set forth in US. application Ser. No. 4-81,- 908, filed Aug. 23, 1965. The sympathomimetic amines, epinephrine and norepinephrine as well as isoproterenol are well known in the art and their properties and method of preparation can be found in standard references as, for example, the Merck Index, 7th edition (1960).

The compositions of this invention are incorporated into a sterile opthalmic vehicle. Such vehicles are Well known in the art and are fully described in such standard reference works as Remingtons Pharmaceutical Sciences, Martin and Cook, Mack Publishing Co., Easton, 13th 3 edition (1965). The following is a suitable example. (The percentages in the following examples refer to a percent weight by volume.)

Sterile vehicle:

8-hydroxyquinolone sulfate percent 0.01 Sodium bisulfite do 0.3 Phenylmercuric acetate do 0.002 Sodium hydroxide or hydrochloric acid to pH 3.5-6 Water, q.s. ad.

In the foregoing composition the 8-hydroxyquinolone and the sodium bisulfite act as anti-oxidants and can vary tenfold (the former up to about 0.1% and the latter down to about 0.03%.) In addition to these specific anti-oxidants, any opthalmic anti-oxidant can be employed. These are more fully described in Remington (supra).

Phenyl mercuric acetate is employed as a preservative. Any preservative suitable for opthalmic formulation such as those described in Remington (supra) can be employed.

Although the pH of the foregoing sterile vehicle is adjusted using base or acid it should be recognized that standard buffering agents such as those described in Remington (supra) or in the Merck Index, volume 7 (1960), so long as these buffering agents are suitable for opthalmic formulation, can be utilized. Thus a pH range from about 3.5-8 can be employed, although pH within the physiological range is preferred. When employing a buffered system it is preferred to utilize a pH of about 6.0 to about 8. With a buffered system pH is conventionally adjusted by adjusting the concentration and at the time altering the ratio of the buffered tonicity so as to maintain an isotonic solution. Although buffers can be used at varying pH, when pH is less than 6.0, sodium hydroxide or hydrochloric acid can conveniently be employed to adjust the pH. When using a buffered system it is preferred to adjust the range to that of the physiological pH range of about 6 to 7.5 or 8. US. Patent 3,149,035 sets forth suitable sterile vehicles for use, especially when a catechol amine, such as epinephrine, is employed in the compositions of this invention.

The following examples demonstrate various formulations of the anti-glaucoma compositions of this invention:

EXAMPLE I Percent 10,11 dihydro -(3-dimethylaminopropyl)-5,10- epoxy 5H dibenzo[a,d]cycloheptene ll-hy- Water, q.s. ad.

4 EXAMPLE 111 Percent (1) Epinephrine 0.1 10,11 dihydro 5-(3-dimethylaminopropyl)-5,10- epoxy 5H dibenzo[a,d]cycloheptene ll-hydroxy-imino hydrogen maleate 0.02 Boric acid 0.8 Sodium borate 0.6 Oxine sulfate 0.01

Phenylmeruric acetate 0.002

Sodium bisulfite 0.3 Water, q.s. ad.

EXAMPLE IV Percent (1) Epinephrine 0.1 Trans 10,11 dihydro 5-(3-methylamino-propyl)- 5,10 epoxy 11 hydroxy 5H-dibenzo[a,d] cycloheptene hydrogen maleate 0.02 Boric acid 0.8 Sodium borate 0.6 Oxine sulfate 0.01

Phenylmercuric acetate 0.002 Sodium bisulfite 0.3 Water, q.s. ad.

The compositions of this invention can also be administered as opthalmic ointments. These are compounded, for example, by mixing finely milled powdered ingredients with a small amount of white petrolatum and levigating or otherwise mixing until a uniform distribution is achieved. The balance of white petrolatum is added by geometric addition until the desired dosage form is made.

I claim:

1. An anti-glaucoma topical opthalmic composition comprising a topical opthalmic vehicle and 0.01 to 0.2% of a member selected from the group consisting of 10,11- dihydro 5 (3-dimethylaminopropyl)-5,10-epoxy-5H-dibenzo[a,d]cycloheptene-1l-hydroxy-imino, trans 10,1 1-dihydro 5-(3-methylaminopropyl)-5,10-epoxy-1l-hydroxy- 5H-dibenzo[a,d]cycloheptene and a non-toxic acid addition salt thereof.

2. A method for lowering intraocular pressure which comprises applying topically to the eye an effective amount of a composition comprising a topical opthalmic vehicle and 0.01 to 0.2% of a member selected from the group consisting of 10,11 dihydro-5-(3-dimethylaminopropyl)- 5,10 epoxy 5H-dibenzo[a,d]cycloheptene-ll-hydroxyimino, trans 10,11 dihydro-5-(3-methylaminopropyl)-5, 10 epoxy-11-hydroxy-5H-dibenzo[a,d]cycloheptene and a non-toxic acid addition salt thereof.

References Cited UNITED STATES PATENTS 8/1966 Schindler 260570.8

8/1967 Freimiller 260345.2 XR

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Pa t N 3,467,756 Dated September 16,- 1969 Inventor(s) Clement A. Stone It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1 line 16 after "epoxy" insert ll-hydroxyimino line 17, delete "ll-hydroxyimino. Column 2 lines 4-11, structural formula should read:

/ H H CH CH N 2 2 2 \CH Column 2 lines 14-22, structural formula sfiould read:

,CH H CH CH N CH Column 2, name following structural formula II, insert after "epoxy ll-hydroxyimino and delete "ll-hydroxyimino" am after "cycloheptene" Column 3 line 47 after "epoxy" insert 11-hydroxyimino lines 47 and 48 delete "ll--hydroxy--- imino" Column 4 line 5 after "epoxy" insert ll-hydroxyimino lines 5 and 6, delete "ll-hydroxyimino"; line 41 after "epoxy" insert ll-hydroxyimino line 421after "cycloheptene" delete "ll-hydroxyimino"; line 52 after "epoxy" insert ll-hydroxyimino lines 52 and 53 after "cyclo heptene" delete "ll-hydroxyimino".

SIGNED NN'D SEALED L. JUN 2 1970 SEAL Am Ed!!! 1!. Fletcher, Ir. mum E- W JR Matin Offi Commissioner of mu 

